PL203087B1 - Method of administering bisphosphonates - Google Patents

Abstract

Bisphosphonates, in particular more potent N-bisphosphonates such as zoledronic acid and derivatives, can be used with satisfactory results for prolonged inhibition of bone resorption in conditions of abnormally increased bone turnover, e.g. osteoporosis, by intermittent administration, wherein the periods between bisphosphonate administrations are longer than was previously considered appropriate, e.g. a dosing interval of at least about 6 months or less frequently.

Description

Description of the invention

The following invention relates to the use of 1-hydroxy-2- (imidazol-1-yl) ethane-1,1-diphosphonic acid or a pharmaceutically acceptable salt or any hydrate thereof in the manufacture of a medicament for the treatment of conditions associated with abnormal, increased bone turnover (bone remodeling). such as osteoporosis.

Bisphosphonates are widely used to inhibit the activity of osteoclasts (osteoclasts) in a variety of both benign and malignant diseases in which bone resorption is increased. Recently, it has become possible to use bisphosphonates in the long-term treatment of patients suffering from multiple myeloma. Bisphosphonates - compounds that are analogs of pyrophosphates not only reduce the incidence of skeletal injuries, but also thanks to the use of these drugs in patients, clinical benefits and an improvement in the survival rate are observed. Bisphosphonates have the ability to prevent bone resorption in vivo, the therapeutic efficacy of bisphosphonates has also been shown in the treatment of Paget's disease, tumor-induced hypercalcemia, and more recently in the treatment of bone metastases and multiple myeloma (for a review, see Fleisch H., 1997, "Bisphosphonates clinical , in "Bisphosphonates in Bone Diseases. From Laboratory to the Patient. The Parthenon Publishing Group, New York / London, pages 68 - 163). The mechanism by which bisphosphonates inhibit bone resorption is still poorly understood and appears to depend on the type of bisphosphonate compound being tested. Bisphosphonates have been shown to bind strongly to hydroxyapatite crystals in bone, reduce bone turnover and bone resorption; cause a decrease in the level of hydroxyproline or alkaline phosphate in the blood, and additionally inhibit both activation and activity of osteoclasts.

Additionally, the use of bisphosphonates in the treatment of osteoporosis has been proposed. For example, as described in USP 4,812,304 (Procter & Gamble), a method of treating or preventing osteoporosis in humans has been proposed comprising administering to patients suffering from osteoporosis or at risk of osteoporosis a bone cell activating compound and bone resorption polyphosphonates according to a regimen of consists of one or more treatment cycles, wherein each cycle comprises: a) a period of bone activation lasting from about 1 day to about 5 days during which said patients are administered an amount of bone cell activating compound sufficient to activate bone cells followed by b ) a bone resorption inhibition period ranging from about 10 days to about 20 days, during which ethane-1-hydroxy-1,1-diphosphonic acid or a pharmaceutically acceptable salt of this acid is administered daily to said patients in an amount ranging from about 0, 25 mgP / kg / day to about 3.3 mgP / kg / day; this period was followed by a period of c) rest (drug breaks) ranging from about 70 days to about 180 days during which the patients were not receiving compounds that activate bone cells or inhibit bone resorption polyphosphonate compounds.

USP 4,761,406 (Procter & Gamble) also proposes a method of treating osteoporosis in humans and lower animals suffering from or at risk of osteoporosis comprising administering to said patients: human or lower animals an effective dose of bone resorption polyphosphonate according to the following schedule consisting of consecutive periods: during period a) lasting from about 1 day to about 90 days, a limited amount of bone resorption polyphosphonate was administered to these patients daily, this period was followed by a period of b) rest lasting from about 50 days to about 120 days, and period, then c) repeating period a) and b) two or more times; the following patients were observed: increase in net bone mass in humans or animals.

We have now found to our amazement that bisphosphonates, and especially the more potent nitrogen-containing bisphosphonates, can be used to achieve long-term inhibition of bone resorption under conditions of abnormal bone turnover with intermittent administration of compounds in which the intervals between administration of bisphosphonates are longer than previously considered adequate to obtain satisfactory results. the results of the therapy. In particular, and contrary to expectations, we have found that satisfactory treatment results can be obtained even when the dosing intervals significantly exceed the natural cycle of bone remodeling.

The invention relates to the use of 1-hydroxy-2- (imidazol-1-yl) ethane-1,1-diphosphonic acid or a pharmaceutically acceptable salt or any hydrate thereof in the manufacture of a medicament for the treatment of conditions associated with abnormal, increased bone turnover in which the acid is

PL 203 087 B1

1-Hydroxy-2- (imidazol-1-yl) ethane-1,1-diphosphonic acid, or a pharmaceutically acceptable salt thereof, or any hydrate is administered intermittently, with a time interval between drug administrations of at least 6 months.

Preferably, the period between drug doses is at least one year.

Preferably, the use according to the invention is for the prophylactic treatment of osteoporosis and the medicament is administered annually or less frequently.

In another preferred embodiment, the use of the invention is for the prophylactic treatment of osteoporosis and the dosing interval is 18 months, two years or longer.

Preferably, 1-hydroxy-2- (imidazol-1-yl) ethane-1,1-diphosphonic acid or a pharmaceutically acceptable salt thereof or any hydrate is administered parenterally.

In another preferred embodiment, 1-hydroxy-2- (imidazol-1-yl) ethane-1,1-diphosphonic acid or a pharmaceutically acceptable salt or hydrate thereof is administered intravenously, subcutaneously, intramuscularly or transdermally.

Preferably, the medicament is for parenteral administration in unit dosage forms containing from 1 to 10 mg of 1-hydroxy-2- (imidazol-1-yl) ethane-1,1-diphosphonic acid or a pharmaceutically acceptable salt or any hydrate thereof, the dosing interval is at least 6 months.

Preferably, a unit dosage form contains from 1 mg to 5 mg of active ingredient, and the period between dosing doses is 6 months.

In another preferred embodiment, the unit dosage form contains from 2 mg to 10 mg of active ingredient, and the period between dosing of the medicament is one year.

Cases in which abnormal excessive bone turnover occurs that can be treated according to the method of the present invention include: treatment of postmenopausal osteoporosis, e.g., reducing the risk of fractures due to osteoporosis; preventing postmenopausal osteoporosis, e.g., preventing postmenopausal bone loss; treating or preventing male osteoporosis; treating or preventing osteoporosis induced by treatment with corticosteroids or treatment of other forms of bone loss secondary to or caused by the treatment, e.g., treatment involving diphenylhydantoin, thyroid hormone replacement therapy; treatment or prevention of bone loss associated with immobilization and space flight; treatment and prevention of bone loss caused by rheumatoid arthritis, bone formation disorders, hyperthyroidism, anorexia nervosa, organ transplantation, loosening of joint prostheses, and other medical cases. For example, such medical cases may include treating or preventing specific bone erosion in rheumatoid arthritis, treating osteoarthritis, e.g. preventing and treating subchondral bone sclerosis, subchondral bone cysts, bone growth (osteophytes), and treatment of bone sclerosis pain. , e.g., by reducing intraosseous pressure; treatment and prevention of hypercalcaemia caused by excessive bone resorption secondary to hyperparathyroidism, thyrotoxicosis (hyperthyroidism), sarcoidosis or vitamin D hypervitaminosis.

As used herein, the terms "treatment and treatment" refer to both prophylactic and preventive therapy, as well as curative or disease modifying therapy, including treatment of patients at risk of acquiring the disease or suspected of having the disease; and patients who suffer from the disease who have been diagnosed with the disease or have been diagnosed with the existence of specific medical conditions. In a particularly advantageous embodiment, the invention can be used for the prophylactic treatment of osteoporosis and similar diseases. Thus, for example, bisphosphonates may be administered to individuals at risk of developing osetoporosis on a normal basis with dosing intervals of about six months, e.g., bisphosphonates may be routinely administered to postmenopausal women with dosing intervals of every six months or less. , e.g. every year.

According to the present invention, the interval between administration of the doses of bisphosphonates is at least six months, e.g. the formulation is administered once every 180 days or less; it is convenient to administer once a year or every time period comprised between 180 days and one year, e.g. once every 7, 8, 9, 10 or 11 months. Interruptions in the administration that correspond to administration of the drug less frequently than once a year may be utilized, e.g., about once each

For months, or about once every two years, or even less frequently, e.g., a formulation frequency of up to about once every 3 years or even less frequently may be used.

The bisphosphonates used in the present invention are characteristic compounds that inhibit bone resorption. Such compounds are characterized by the presence of two phosphonate groups attached to one carbon atom to form a structure of the "P-C-P type, as for example in a compound of structural formula I:

where:

X is a hydrogen atom, a hydroxyl group, an amino group, an alkanoyl group, or an amino group mono- or disubstituted with a C1-C4 alkyl group;

R is a hydrogen atom or a C1-C4 alkyl group and

Rx is an arbitrarily substituted hydrocarbyl group or the pharmaceutically acceptable salts of the described compounds or any of the hydrates of these compounds.

Thus, for example, the bisphosphonates that can be used in the present invention may include the following compounds or pharmaceutically acceptable salts thereof, or any of the hydrates of these compounds: 3-amino-1-hydroxypropane-1,1-diphosphonic acid (pamidronic acid), e.g. pamidronate (APD); 3- (N, N-dimethylamino) -1-hydroxypropane-1,1-diphosphonic acid, e.g. dimethyl-APD, 4-amino-1-hydroxybutane-1,1-diphosphonic acid (alendronic acid), e.g. alendronate; 1 hydroxy-ethidien bisphosphonic acid, e.g., etidronate; 1-hydroxyl-3- (methylpentylamino) propylidene bisphosphonic acid, (ibandronic acid); e.g., ibandronate; 6-amino-1-hydroxyhexane-1,1-diphosphonic acid, e.g. amino-hexyl-BP; 3- (N-methyl-N-n-pentylamino) -1-hydroxypropane-1,1 e.g. acid methyl-pentyl-APD (= BM 21.0955); 1-hydroxy-2- (imidazol-1-yl) -ethane-1,1, e.g. zoledronic acid; 1-Hydroxy-2- (3-pyridyl) ethane-1,1-diphosphonic acid (acid e.g. risedronate, including the N-methylpyridine salts of said compounds for example N-methylpyridine iodides such as NE-10244 or NE-10446; 1- (4-chlorophenylthio) -methane-1,1-diphosphonic acid (tiludronic acid), e.g. tiludronate; 3- [N- (2-phenylthioethyl) -N-methylamino] -1-hydroxypropane-1,1- diphosphonic acid; 1-hydroxy-3- (pyrrolidin-1-yl) propane-1,1-diphosphonic acid, e.g. EB 1053 (Leo); 1- (N-phenylaminothiocarbonyl) methane-1,1-diphosphonic acid, e.g. FR 78844 (Fujisawa); 5-benzoyl-3,4-dihydro-2H-pyrazole-3,3-diphosphonic acid tetraethyl ester e.g. U-81581 (Upjohn); 1-hydroxy-2- (imidazo [ 1,2-a] pyrid-3-yl) ethane-1,1-diphosphonic acid e.g. YM 529 and 1,1-dichloromethane-1,1-diphosphonic acid (clodronic acid) e.g. clodronate, YM175.

The bisphosphonate compounds that can be used in the invention below are N-bisphosphonates, i.e. compounds which, in addition to their characteristic twin bisphosphonate environment (e.g. the "PCP system), contain a side chain containing a nitrogen atom, e.g. compounds of the structural formula I ' :

- diphosphonic,

-diphosphonic, risedron),

PL 203 087 B1 where:

X is a hydrogen atom, a hydroxyl group, an amino group, an alkanyl group, or an amino group mono- or disubstituted with a C1-C4 alkyl group;

R is a hydrogen atom or a C1-C4 alkyl group and

Rx 'is a side chain containing an arbitrarily substituted amino group or a nitrogen-containing heterocyclic substituent (including aromatic nitrogen-containing heterocyclic substituents), or pharmaceutically acceptable salts of the described compounds, or any hydrate of these compounds.

Thus, for example, suitable bisphosphonates for use in the present invention may include the compounds listed below or their pharmaceutically acceptable salts or any of the hydrates of these compounds: 3-amino-1-hydroxypropane-1,1-diphosphonic acid (pamidronic acid), e.g. pamidronate (APD); 3- (N, N-dimethylamino) -1-hydroxypropane-1,1-diphosphonic acid, e.g. dimethyl-APD, 4-amino-1-hydroxybutane-1,1-diphosphonic acid (alendronic acid), e.g. alendronate; 1-hydroxyl-3- (methylpentylamino) propylidene bisphosphonic acid, (ibandronic acid); e.g., ibandronate; 6-amino-1-hydroxyhexane-1,1-diphosphonic acid, e.g. amino-hexyl-BP; 3- (N-methyl-N-n-pentylamino) -1-hydroxypropane-1,1-diphosphonic acid, e.g. methylpentyl-APD (= BM 21.0955); 1-hydroxy-2- (imidazol-1-yl) -ethane-1,1-diphosphonic acid, e.g. zoledronic acid; 1-hydroxy-2- (3-pyridyl) ethane-1,1-diphosphonic acid (risedronic acid) e.g. risedronate, including the N-methylpyridine salts of the compounds mentioned e.g. N-methylpyridine iodides such as NE-10244 or NE -10446; 3- [N- (2-phenylthioethyl) -N-methylamino] -1-hydroxypropane-1,1-diphosphonic acid; 1-hydroxy-3- (pyrrolidin-1-yl) -propane-1,1-diphosphonic acid. e.g. EB 1053 (Leo); 1- (N-phenylaminothiocarbonyl) methane-1,1-diphosphonic acid, e.g. FR 78844 (Fujisawa); 5-benzoyl-3,4-dihydro-2H-pyrazole-3,3-diphosphonic acid tetraethyl ester, e.g. U-81581 (Upjohn) and 1-hydroxy-2- (imidazo [1,2-a] pyrid- 3-yl) ethane-1,1-diphosphonic e.g. YM 529.

One very good example of N-bisphosphonate compounds that can be used in the following invention includes compounds of structural formula II:

³ (OR) ₂

p (° R> ₂ o

where:

Het is an imidazole, oxazole, isoxazole, oxodiazole, thiazole, thiadiazole, pyridine, 1,2,3-triazole, 1,2,4-triazole substituent or a benzimidazole radical that is optionally substituted with an alkyl, alkoxy, halogen, hydroxyl group , carboxyl, amino optionally substituted with an alkyl or alkanoyl radical or a benzyl radical optionally substituted with an alkyl, nitro, amino or aminoalkyl group;

A is a straight or branched chain, saturated or unsaturated hydrocarbon chain containing from 1 to 8 carbon atoms,

X 'is a hydrogen atom, optionally an alkanoyl group, or an amino group optionally substituted with alkyl or alkanoyl radicals, and

R is a hydrogen atom or an alkyl group, or a pharmaceutically acceptable salt of the described compounds.

Another very good example of bisphosphonate compounds, the use of which is possible in the present invention, includes compounds of structural formula III:

PL 203 087 B1

where:

Het 'is a substituted or unsubstituted heteroaromatic five-membered ring selected from imidazole, imidazolinyl, isoxazole, oxazolyl, oxazolinyl, thiazolyl, thiazoinyl, triazolyl, oxadiazolyl and thiadiazolyl groups, in which at least the hydrogenated ring may be selected and in which the hydrogenated ring may be selected. a group comprising C1-C4 alkyl, C1-C4 alkoxy, phenyl, cyclohexyl, cyclohexylmethyl, halogen, and amino groups, wherein two adjacent Het alkyl substituents collectively form a second ring;

Y is a hydrogen atom or a C1-C4 alkyl substituent,

X is a hydrogen atom, a hydroxyl group, optionally an amino group or an amino group substituted with a C1-C4 alkyl substituent, and

R is hydrogen or a C1-C4 alkyl substituent, or pharmaceutically acceptable salts or isomers of the compounds described.

Another very good example of bisphosphonate compounds which can be used in the following invention includes compounds of structural formula IV:

ABOUT

where:

Het '' is an imidazolyl, 2H-1,2,3-, 1H-1,2-4 or 4H-1,2-4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl or thiadiazolyl radical which is not substituted or mono or di substituted on carbon by lower alkyl, lower alkoxy and / or halogen, by hydroxy, by di-lower alkylamino, by lower alkylthio and / or halogen, and is N-substituted on the corresponding the nitrogen atom by a lower alkyl group or a phenyl-lower alkyl group which in turn may be mono- or di-substituted on the phenyl moiety by a lower alkyl group, a lower alkoxy group and / or a halogen atom, and

R2 is a hydrogen atom, a hydroxyl group, an amino group, a lower thioalkyl group or a halogen atom, the lower radicals contain and include up to 7 carbon atoms, or the pharmaceutically acceptable salts of the described compounds.

Examples of N-bisphosphonate compounds that may be used in the present invention include:

2- (1-methylimidazol-2-yl) -1-hydroxyethane-1,1-diphosphonic acid; 2- (1-benzylimidazol-2-yl) -1-hydroxyethane-1,1-diphosphonic acid; 2- (1-methylimidazol-4-yl) -1-hydroxyethane-1,1-diphosphonic acid; 1-amino-2- (1-methylimidazol-4-yl) ethane-1,1-diphosphonic acid; 1-amino-2- (1-benzylimidazol-4-yl) ethane-1,1-diphosphonic acid; 2- (1-methylimidazol-2-yl) ethane-1,1-diphosphonic acid;

2- (1-benzylimidazol-2-yl) ethane-1,1-diphosphonic acid; 2- (imidazol-1-yl) -1-hydroxyethane-1,1-diphosphonic acid; 2- (imidazol-1-yl) ethane-1,1-diphosphonic acid;

2- (4H-1,2-4-triazol-4-yl) -1-hydroxyethane-1,1-diphosphonic acid;

2- (thiazol-2-yl) ethane-1,1-diphosphonic acid;

2- (imidazol-2-yl) ethane-1,1-diphosphonic acid;

2- (2-methylimidazol-4 (5) -yl) ethane-1,1-diphosphonic acid;

2- (2-phenyimidazol-4 (5) -yl) ethane-1,1-diphosphonic acid;

2- (4,5-dimethylimidazol-1-yl) -1-hydroxyethane-1,1-diphosphonic acid and 2- (2-methylimidazol-4 (5) -yl) -1-hydroxyethane-1,1-diphosphonic acid and pharmaceutically acceptable salts of the described compounds

The N-bisphosphonate compound most preferred for use in the present invention is 2- (imidazol-1-yl) -1-hydroxyethane-1,1-diphosphonic acid (zoledronic acid) and the pharmaceutically acceptable salts thereof.

Pharmaceutically acceptable salts are those formed with bases, metal salts belonging to Ia, Ib, IIa and IIb of the Periodic Table group are preferred, including alkali metal salts, e.g. potassium and especially sodium salts, or alkaline earth metal salts, preferred are calcium or magnesium; also ammonium salts formed with ammonia or organic amines.

Particularly preferred pharmaceutically acceptable salts are those in which one, two, three or four, especially one or two acidic hydrogen atoms of the bisphosphonate acid have been replaced by suitable cations, especially sodium, potassium or ammonium, especially sodium.

A very preferred group of pharmaceutically acceptable salts are those characterized by the presence of one acidic hydrogen atom and one pharmaceutically acceptable cation, especially sodium, in each of the acidic phosphono groups.

The bisphosphonate acid derivatives especially mentioned above are well described in the literature. This applies to their manufacture (see e.g. EP-A-513760, pages 13 - 48). For example, 3-amino-1-hydroxypropane-1,1-diphosphonic acid is prepared as described in U.S. Patent 3,962,432, as is the disodium salt as described in U.S. Patent Nos. 4,639,338 and 4,711,880, 1-hydroxy-2-acid. - (imidazol-1-yl) -ethane-1,1-diphosphonic acid is prepared as described in e.g. US Patent 4,939,130.

Bisphosphonates (hereinafter referred to as agents of the invention) may be used in the form of isomers or mixtures of isomers as appropriate; especially as optical isomers such as enantiomers, or diastereoisomers or geometric isomers, especially cis-trans isomers. Optical isomers are obtained as pure antipodes and / or as racemic mixtures.

The agents according to the invention can also be used in the form of the hydrates of the compounds mentioned or contain solvents used for their crystallization.

The agents of the invention are preferably used in the form of pharmaceutical compositions containing a therapeutically effective amount of the active ingredient optionally together with or in admixture with an organic or inorganic, solid or liquid, pharmaceutically acceptable carrier; which is suitable for the administration of the drug.

The agents of the invention may be administered as such or in combination with other bone tissue activators, either in fixed combinations or separately both physically and in terms of time, including hormones such as steroid hormones, e.g. estrogen, partial estrogen antagonists or a combination of estrogen, gestagen; calcitonin or an analog or derivative of calcitonin, e.g., eel or human salmon calcitonin, parathyroid hormone or its analog, e.g. PTH (1-84), PTH (1-34), PTH (1-36), PTH (1-38) , PTH (1-31) NH2 or PTS 893; SERMs (Selective Estrogen Receptor Modulators) e.g. raloxifene, lasofoxifene, TSE-424, FC1271, Tibolone (Lival®); vitamin D or its analog. Such additional bone tissue activator drugs may be administered more frequently than bisphosphonates.

The pharmaceutical compositions can be, for example, compositions for enteral administration, such as oral administration, rectal administration, administration by inhalation spray or nasal administration; a composition for parenteral administration, such as intravenous or subcutaneous administration, or a composition for transdermal administration (e.g., passive or ionophoretic).

PL 203 087 B1

Pharmaceutical compositions adapted for oral or parenteral (especially intravenous, subcutaneous, intramuscular or transdermal) administration are preferred. Intravenous and oral, primarily and mainly intravenous, mode of drug administration is considered to be of particular importance. It is preferable to administer the active bisphosphonate in a form intended for parenteral administration, most preferably intravenously.

The particular mode of drug administration and dose can be selected by the attending physician taking into account the relevant specific conditions of the patient, particularly age, weight, lifestyle, activity level, hormonal status (e.g. postmenopausal) and bone mineral density.

The dosage amount of the agents of the invention may depend on various factors such as the efficacy and duration of action of the active ingredient, e.g., the relative potency of the bisphosphonate used, the mode of administration, the species of the warm-blooded animal, and / or the sex, age, weight, and individual condition of the warm-blooded animal. .

Typically the dosage amount is such that a single dose of the bisphosphonate active ingredient is from 0.005 to 20 mg / kg, especially from 0.01 to 10 mg / kg, is administered to a warm-blooded animal weighing about 75 kg.

The term "mg / kg" means milligram of the drug per kilogram of body weight in a mammal - including a human being treated.

The dose mentioned above is conventionally administered intermittently with a period of time between doses being at least 6 months. The period between administration of the bisphosphonates may be longer, e.g. it is convenient to administer the drug once a year, once every 18 months, or once every two years, or even an even longer period of time, and any time therebetween.

Unit dosage form preparations preferably contain an amount of active compound from about 1% to about 90%, non-unit dosage preparations preferably contain an amount of active compound from about 0.1% to about 20%. Unit dosage forms in the form of ampoules containing an infusion solution or a solid preparation intended for the preparation of infusions, capsules, tablets or dragees contain, for example, from about 0.5 mg to about 500 mg of active compound. The actual dose administered should, among other factors, depend on the potency of the bisphosphonate compound employed, the length of the interval between the doses administered, and the route of administration. Thus, unit dose size is typically lower for compounds of greater potency and larger for the longer interval between dosing. For example, for the more potent N-bisphosphonates such as zoledronic acid, a single dose is from about 1 to about 10 mg for parenteral administration, e.g., by the intravenous route. For example, also for the more potent N-bisphosphonates when administered parenterally, once every 6 months, a single dose may be from about 1 to about 5 mg; whereas for parenteral drug administration once a year the dose may be from about 2 mg to about 10 mg.

The unit dosage forms can be administered as single doses or divided doses, i.e., doses in which a unit dosage form is divided into two or more equal or unequal parts and wherein said parts are administered to a patient at the same time and at overlapping intervals. time or at separate times. When a unit dosage form is administered as a divided dose at separate times, the time interval between administering the individual divided doses can be from hours, e.g., one hour to about one month (about 30 days). According to the present invention, the time interval between the administration of the last part of a divided dose and the administration of the first part of a subsequent, next, divided dose is at least 6 months or longer, e.g. about 1 year.

Thus, for example, a single dose of 10 mg may be administered as two equal parts administered with an interval between the administrations of each dose portion of from about 1 week to about 1 month, e.g., about 2 weeks. Alternatively, for example, a single dose of 5 mg may be administered as two unequal parts of 4 mg and 1 mg (or 3 mg and 2 mg) over a period ranging from 1 to 3 days up to 1 to 3 weeks, e.g. of about 1 week between dose administrations.

Pharmaceutical preparations intended for enteral and parenteral administration are, for example, in the form of dragees, tablets or capsules, and also ampoules. They are prepared in a manner known per se, for example by conventional mixing, granulating, confectioning, dissolving or lyophilizing processes. For example, pharmaceutical preparations intended for oral administration can be prepared by combining the active ingredient with a solid carrier, if appropriate, by granulating the resulting mixture and processing the mixture or the granulate; if desired or necessary after adding suitable processing aids into tablets or dragee cores.

Suitable carriers are especially fillers such as sugars, for example lactose, sucrose, mannitol or sorbitol, cellulose preparations, binders such as starch pastes using, for example, corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose and / or polyvinylpyrrolidone. if desired, disintegrating agents such as the above-mentioned starches, and also carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar or alginic acid, or a salt thereof, such as sodium alginate. Additives are especially flow regulators and lubricants, for example silicic acid, talc, stearic acid and its salts, such as magnesium or calcium stearate and / or polyethylene glycol. Dragee cores may be protected with a suitable coating which may be resistant to gastric juice, for this purpose, for example, concentrated sugar solutions may be used which may optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide or solutions of varnishes in suitable organic solvents or, to obtain gastric acid-resistant coatings, solutions of suitable cellulose preparations such as cellulose acetyl phthalate or hydroxypropyl methylcellulose phthalate. Coloring substances or pigments may be added to the tablet or dragee coatings, for example for identification purposes or to distinguish between different doses of active ingredient.

Other pharmaceutical preparations intended for oral administration are dry-fill capsules made of gelatin, and soft, sealed capsules made of gelatin and a plasticizer such as glycerol and sorbitol. Dry-filled capsules may contain the active ingredient in the form of granules, for example admixed with fillers such as lactose, binders such as starch, and / or glidants such as talc or magnesium stearate, and, if appropriate, stabilizers. In soft capsules it is preferred that the active ingredient is dissolved or suspended in a suitable liquid such as fatty oils, paraffin oil or liquid polyethylene glycols, and in addition, stabilizers may be added to the formulation.

Preparations for parenteral administration, especially injectable fluids, are effective for administration such as intramuscular, intraperitoneal, intranasal, intradermal, subcutaneous or preferably intravenous administration. Preference is given to isotonic aqueous solutions or suspensions which may be prepared prior to use, for example, from a lyophilized preparation which contains only the active ingredient or the active ingredient together with a pharmaceutically acceptable carrier, or from concentrated solutions. The pharmaceutical preparations described can be sterilized and / or can contain auxiliary substances, for example preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffers.

Formulations suitable for transdermal application include an effective amount of the active ingredient in combination with a carrier. Suitable carriers include absorbable, pharmaceutically acceptable solvents to facilitate passage of the drug through the skin of the patient. Typically, transdermal administration employs bands with a backing, a reservoir containing the compound optionally with a carrier, optionally a rate-regulating barrier such that the active ingredient is applied to the patient's skin at a controlled and predefined rate over an extended period of time, and suitable means to secure the entire surface. the set on the skin.

Illustrative of the above-described invention are given below.

In the following examples, the term "active ingredient is to be understood as any compound of the bisphosphonate acid derivatives mentioned above useful for the present invention.

Examples

P r z k ł a d 1

Capsules containing coated granules of the active ingredient, e.g. disodium pamidronate pentahydrate, as an active ingredient:

PL 203 087 B1

Pellet core:

Active ingredient (ground) 197.3 mg

Microcrystalline cellulose (Avicel® PH 105) 52.7 mg

250.0 mg

Outer shell: Cellulose HP-M 603 Poly (ethylene glycol) Talc mg 2.0 mg 8.0 mg

270.0 mg + Gastric acid-resistant outer shell:

Eudragit® L 30 D (solid) 90.0 mg

Triethyl citrate 21.0 mg

Antifoam® AF 2.0 mg

Water

Talc 7.0 mg

390 mg

The mixture of disodium pamidronate with Avicel® PH 105 is wetted with water and kneaded, pressed and formed into balls. The dried pellets are then successively coated in a fluidized bed with an outer coating containing cellulose HP-M 603, polyethylene glycol (PEG) 8000 and talc, and an aqueous gastric resistant coating solution containing Eudragit® L 30 D, triethyl citrate and Antifoam ® AF. The coated pellets are powdered with talc and are filled into capsules (capsule size 0) using a commercial capsule filling machine, e.g. from Hofliger and Karg.

Example 2: A uniform adhesive transdermal delivery system containing, for example, 1-hydroxy-2- (imidazol-1-yl) -ethane-1,1-diphosphonic acid as an active ingredient:

Composition:

Polyisobutylene (PIB) 300 5.0 g (Oppanol B1, BASF)

PIB 35,000 3.0 g (Oppanol B1O, BASF)

PIB 1,200,000 9.0 g (Oppanol B1OO, BASF)

Hydrogenated hydrocarbon resin 43.0 g (Escorez 5320, Exxon)

1-dodecyllazocycloheptan-2-one 20.0 g (Azone, Nelson Res., Irvine / CA)

Active ingredient 20.0 g

Total 100.0 g

Preparation:

The above-mentioned components are dissolved together in 150 g of the peculiar boiling point crude oil fraction 100 - 125 in a grinding bed apparatus. The solution is applied to a polyester layer (Hostaphan, Kalle) using a 300 mm arm layering device, resulting in a coating thickness of approximately 75 g / m ² . After drying (15 minutes at 60 ° C), a silicon-treated polyester layer (thickness 75 mm, Laufenberg) is applied as a photo-protective layer. In the obtained arrangement, holes of the desired shape and size from 5 to 30 cm ^{2 are} cut using a cutting device. The obtained system is individually tightly packed in paper sachets covered with aluminum foil.

Example 3: Vial containing 1.0 mg of dry, lyophilized 1-hydroxy-2- (imidazol-1-yl) -ethane-1,1-diphosphonic acid (a mixture of the acid's sodium salts). After dilution with 1 ml of water, a solution is obtained for intravenous infusion (concentration 1 mg / ml).

PL 203 087 B1

Composition:

Active ingredient (free diphosphonic acid) Mannitol

Trisodium citrate x 2 H2O Water

Water for injection

1.0 mg

46.0 mg approx. 3.0 mg ml 1 ml

In 1 ml of water, the active ingredient is titrated with trisodium citrate x 2 H2O to pH = 6.0. Then mannitol is added and the solution is lyophilized and the lyophilisate is filled into a vial.

Example 4: An ampoule containing an active ingredient, for example disodium pamidronate pentahydrate dissolved in water. The solution (concentration 3 mg / ml) is intended for intravenous infusion after dilution.

Composition:

Active ingredient (5.0 mg of anhydrous active ingredient) Mannitol

Water for injections

19.73 mg

250.0 mg 5 ml

Example 5 Treatment of patients

An international, randomized, double-blind, placebo-controlled, parallel group, variable dose, safety and efficacy study with intravenous high dose intravenous administration of the drug zoledronate in the treatment of postmenopausal osteoporosis.

This study examined the dose size and dosing regimen during a 12-month study conducted with zoledronic acid, and the study was conducted in patients suffering from postmenopausal osteoporosis. Three hundred and fifty-one patients were randomly assigned to six study groups. Patients recently treated with bone activating drugs, e.g. bisphosphonates, estrogen, cacitonin, raloxifene, or with a history of metabolic diseases were excluded from the study. All patients were assessed at baseline and at three-month visits. Zoledronic acid or a placebo was given as a high dose by intravenous injection into peripheral blood vessels over 5 minutes at each visit to the physician.

Efficacy was assessed by measuring the percent change in baseline bone mineral density (BMD) as measured by dual energy X-ray absorptiometry (DEXA) and placebo-controlled studies at 6, 9 and 12 months.

As a special precaution, hip biopsies were performed on a subset of patients from all study groups after 12 months; X-rays of the thoracic and lumbar spine of all examined patients were assessed at the initial level and after 12 months for the occurrence of vertebral fractures.

Additionally, every 3 months the degree and duration of suppression of biochemical markers of bone turnover was obtained and determined in a central laboratory: parathyroid hormone (PTH), bone-specific alkaline phosphatase (BSAP), serum C-telopeptide (CTX) concentration, and serum osteocalcin. blood, urinary N-telopeptide (NTX) to urinary creatinine ratio, urine deoxypyridonoline to urine creatinine ratio, urine pyridinoline to urine creatinine ratio,

Study groups • Placebo • 0.25 mg zoledronic acid - administered every 3 months • 0.5 mg zoledronic acid - administered every 3 months • 1.0 mg zoledronic acid - administered every 3 months • 2.0 mg zoledronic acid - administered every 6 months • 4.0 mg zoledronic acid - administered every 12 months

The results obtained after 12 months indicate that the percentage of change from baseline in BMD among the treated groups is significantly greater (p <0.001) than in the case of placebo and is not different from each other.

PL 203 087 B1

Summary of step-by-step multiple comparisons of zoledronate active doses to placebo as percent change from baseline in lumbar spine bone mineral density; posterior anterior (L1-L4) at 12 months Confirmatory analysis ITT population Number another one step The most contrasting combination Difference Standards error of difference Confidence lower limit of 97.5% P value 1 Zoledronate 4 x 0.25 mg - placebo 5.1 0.5 3.7 <0.001 2 Zoledronate 4 x 0.5 mg - placebo 4.9 0.6 3.5 <0.001 3 Zoledronate 1 x 4.0 mg - placebo 4.6 0.3 3.3 <0.001 4 Zoledronate 4x1.0 mg - placebo 4.5 0.5 3.2 <0.001 5 Zoledronate 2 x 2.0 mg - placebo 4.2 0.7 3.1 <0.001

Note: Step-by-step comparison of zoledronate active dose versus placebo for a one-way multiple test at the alpha level of 0.25% adjusting the multiple comparison according to Marcus, Peritz and Gabriel (1976).

Bone mineral density was increased compared to placebo administration in the spine, hip, radius and "whole body." The suppression of biochemical markers of bone formation and bone resorption confirmed and was consistent with the BMD results, indicating a reduction in bone turnover to pre-menopausal values at the dosing intervals of 6 and 12 months.

The results of the BMD study indicate that administration of doses of zoledronic acid over periods as infrequent as 6 or 12 months can safely lead to a statistically significant result and a medically significant increase in bone mass. In our opinion, the above data also indicate that the further preservation of the new bone material beyond one year, without the administration of additional doses of the drug, is likely, or it is possible to further increase bone mass. We believe that re-treatment in cycles of 6 or 12 months, or less frequent dosing, can also lead to a further increase in BMD. In line with our expectations, the reduction of the risk of osteoporotic fractures will accompany the increase in bone mass.

Claims (9)

1. Use of 1-hydroxy-2- (imidazol-1-yl) ethane-1,1-diphosphonic acid or a pharmaceutically acceptable salt or any hydrate thereof in the manufacture of a medicament for the treatment of conditions associated with abnormal, increased bone turnover in which the acid 1 -hydroxy-2- (imidazol-1-yl) ethane-1,1-diphosphonic acid, or a pharmaceutically acceptable salt thereof, or any hydrate is administered intermittently with an interval between administrations of drug doses of at least 6 months. 2. The use according to claim 1 The method of claim 1, wherein the period between drug administrations is at least one year. 3. Use according to claim 1 The medicament of claim 1 for the prophylactic treatment of osteoporosis, the medicament being administered annually or less frequently. 4. The use according to claim 1 The drug administration according to claim 1, for the prophylactic treatment of osteoporosis, and the dosing interval is 18 months, two years or longer. 5. Use according to claim 1 A method as claimed in any one of the preceding claims, wherein the 1-hydroxy-2- (imidazol-1-yl) ethane-1,1-diphosphonic acid or a pharmaceutically acceptable salt thereof or any hydrate is administered parenterally. 6. Use according to claim 1 A compound according to any of the preceding claims, wherein 1-hydroxy-2- (imidazol-1-yl) ethane-1,1-diphosphonic acid or a pharmaceutically acceptable salt thereof or any hydrate is administered intravenously, subcutaneously, intramuscularly or transdermally. PL 203 087 B1 Use according to claim 1 2. The medicament as claimed in claim 1, characterized in that the medicament is for parenteral administration in unit dosage forms containing from 1 to 10 mg of 1-hydroxy-2- (imidazol-1-yl) ethane-1,1-diphosphonic acid or a pharmaceutically acceptable salt or any hydrate thereof. wherein the time interval between dosing doses is at least 6 months. 8. Use according to claim 1 The method of claim 7, characterized in that the unit dosage form contains from 1 mg to 5 mg of the active ingredient, and the period between administration of drug doses is 6 months. Use according to claim 1 7. The method of claim 7, wherein the unit dosage form contains from 2 mg to 10 mg of the active ingredient, and the period between administration of drug doses is one year.